Richa Bhatia, MD, DFAPA

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.